1. Field of the Invention
The present invention relates to pharmaceutical compositions containing tiludronate hydrates for oral administration and a process for their preparation. The pharmaceutical compositions are stable and possess therapeutic properties permitting their use in the treatment of osteoporosis, rheumatoid polyarthritis and Paget's disease.
2. Reported Developments
Bisphosphonic acid derivatives having the formula ##STR1## in which R.sub.1 represents a hydrogen atom, a halogen atom, a hydroxyl, an amino or a dialkyl(C.sub.1 -C.sub.4)amino, and
R.sub.2 represents a halogen atom, a linear alkyl containing from 1 to 5 carbon atoms which is unsubstituted or substituted by a chlorine atom, a hydroxyl, an amino or a dialkyl(C.sub.1 -C.sub.4)amino, or PA1 R.sub.2 represents a phenoxy, a phenyl, a thiol, a phenylthio, a chlorophenylthio, a pyridyl or a thiomorpholin-4-yl, PA1 and their salts with pharmaceutically acceptable mineral or organic acids, are known compounds having been disclosed in the following patents: PA1 (a) reacting tiludronic acid with sodium hydroxide in an aqueous solution and then adding a non-solvent such as acetone to cause precipitation of the tetrahydrate; or PA1 (b) subjecting disodium tiludronate hemihydrate to an excess of water; or PA1 (c) subjecting disodium tiludronate monohydrate to an excess of water.
BE No. 902308 PA0 BE No. 865434 PA0 FR No. 2531088 PA0 JP No. 55-98193 PA0 BE No. 822930 PA0 DE No. 2130794 PA0 EP No. 203649 PA0 EP No. 162510 PA0 EP No. 39033 PA0 EP No. 100718 PA0 EP No. 186405 PA0 FR No. 2525223 PA0 U.S. Pat. No. 4,134,969 PA0 U.S. Pat. No. 4,578,376 PA0 U.S. Pat. No. 4,621,077 PA0 U.S. Pat. No. 4,980,171 PA0 U.S. Pat. No. 5,405,994 PA0 WO No. 86/00902 PA0 WO No. 87/03598
The compounds have been described as useful in the oral treatment of bone diseases and/or articular complaints of the arthritis type. Among the compounds is tiludronic acid, i.e., 4-chlorophenylthiomethylenebisphosphonic acid, and its disodium salt having the chemical structure ##STR2## which has been extensively investigated for the development of a drug useful in the treatment of rheumatoid polyarthritis, Pagers disease and osteoporosis.
U.S. Pat. No. 5,405,994 discloses two forms of disodium tiludronate: disodium tiludronate hemihydrate and disodium tiludronate monohydrate. Disodium tiludronate hemihydrate is prepared in situ from an aqueous solution of tiludronic acid by the addition of a sufficient amount of sodium hydroxide to being the pH to between 4.6 and 4.8. Disodium tiluclronate monohydrate is prepared by heating disodium tiludronate hemihydrate in aqueous solution at a temperature of between 60.degree. C. to 90.degree. C. for about 2 to 24 hours, cooling the solution to a temperature of between room temperature and 5.degree. C., filtering off the precipitate formed and then drying the precipitate.
The preparation of 4-chlorophenylthiomethylenebisphosphonate, disodium 4-chloro-phenylthiomethylenebisphosphonate hemihydrate and disodium 4-chlorophenylthiomethylene-bisphosphonate monohydrate is described as follows.